WO2007089715A2 - Méthode de traitement pour douleur neuropathique - Google Patents

Méthode de traitement pour douleur neuropathique Download PDF

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Publication number
WO2007089715A2
WO2007089715A2 PCT/US2007/002422 US2007002422W WO2007089715A2 WO 2007089715 A2 WO2007089715 A2 WO 2007089715A2 US 2007002422 W US2007002422 W US 2007002422W WO 2007089715 A2 WO2007089715 A2 WO 2007089715A2
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Prior art keywords
alkyl
group
substituted
compound
formula
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PCT/US2007/002422
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English (en)
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WO2007089715A3 (fr
Inventor
Kevin R. Lynch
Timothy L. Macdonald
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University Of Virginia Patent Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by University Of Virginia Patent Foundation filed Critical University Of Virginia Patent Foundation
Priority to JP2008552487A priority Critical patent/JP2009528274A/ja
Priority to AU2007209961A priority patent/AU2007209961A1/en
Priority to BRPI0707281-3A priority patent/BRPI0707281A2/pt
Priority to MX2008009579A priority patent/MX2008009579A/es
Priority to CA002640366A priority patent/CA2640366A1/fr
Priority to EP07717121A priority patent/EP1986623A2/fr
Publication of WO2007089715A2 publication Critical patent/WO2007089715A2/fr
Publication of WO2007089715A3 publication Critical patent/WO2007089715A3/fr
Priority to IL193040A priority patent/IL193040A0/en
Priority to US12/179,816 priority patent/US8008286B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention relates to sphingosine 1 -phosphate analogs, with activity at one or more sphingosine 1 -phosphate receptors, which are useful for preventing and treating neuropathic pain.
  • Sphingosine- 1 -phosphate is a lysophospholipid mediator that evokes a variety of cellular responses by stimulation of five members of the endothelial cell differentiation gene (EDG) receptor family.
  • EDG receptors are G-protein coupled receptors (GPCRs) and on stimulation propagate second messenger signals via activation pf heterotrimeric G-protein alpha (G ⁇ ) subunits and beta-gamma (Gp 7 ) dinners.
  • Sphingosine-1-phos ⁇ hate (S IP) has been demonstrated to induce cellular processes, including those that result in platelet aggregation, cell proliferation, cell morphology, tumor-cell invasion, endothelial cell chemotaxis and endothelial cell in vitro angiogenesis. Therefore, SlP receptors have been targets for therapy of, for example, wound healing and tumor growth inhibition.
  • Sphingosine- 1 -phosphate is • believed to signal cells in part via a set of G protein-coupled receptors named SlPi, SlP 2 , SlP 3 , S lP 4 , and SlP 5 (formerly EDGl, EDG5, EDG3, EDG6 and EDG8, respectively).
  • SlP receptors have been selected as drug targets because the individual receptors are both tissue and response specific. Tissue specificity of the SlP receptors is desirable because development of an agonist or antagonist selective for one receptor localizes the cellular response to tissues containing that receptor, limiting unwanted side effects. Response specificity of the SlP receptors is also of importance because it allows for the development of agonists or antagonists that can initiate or suppress certain cellular responses without affecting other responses. For example, the response specificity of the SlP receptors could allow for an SlP mimetic that initiates platelet aggregation without affecting cell morphology.
  • Neuropathic pain is characterized by its chronic nature, an absence of an obvious direct cause ⁇ e.g., tissue damage), hyperalgesia, or allodynia.
  • Hyperalgesia is an exaggerated response to a painful stimulus. Allodynia is the perception of normal stimuli as painful (examples include the touch of clothing, warm or cool air, etc.).
  • Neuropathic pain can be a sequel to nerve damage in an extremity such as an arm, or more often, a leg.
  • Precipitating events can include trauma, e.g., motor vehicle accidents or amputations (e.g., phantom limb pain).
  • Neuropathic pain can occur due to an adverse effect of drug therapies, e.g., vincristine or paclitaxel (TaxolTM), or can occur as a component of disease pathologies, such as diabetes type 1 or type 2, shingles, HIV-I infections, etc.
  • drug therapies e.g., vincristine or paclitaxel (TaxolTM)
  • TexolTM paclitaxel
  • neuropathic pain does not respond to opiates or non-steroidal anti- inflammatory drugs such as aspirin. Treatment of neuropathic pain is an important unmet medical need and this invention addresses that need.
  • the present invention provides, in one aspect, compounds and methods useful for preventing and treating pain in a subject in need thereof.
  • the method includes administering to said subject an effective amount of a compound having formula (I) or formula (II):
  • R 4 and R 7 are independently CH, or CH 2 , R 5 is C, CH, or N, R 6 is CH, CH 2 ,
  • R 3 is hydrogen, or an alkyl group.
  • X is selected from hydroxyl (-OH), phosphate (-OPO 3 H 2 ), phosphonate
  • R 1 is selected from the group consisting of hydrogen, halo, tri-fluoromethyl, (Ci-Cio)-alkyl, (Ci-Cio) alkyl substituted with halo, hydroxy, alkoxy, or cyano
  • R 2 is selected from the group consisting of (Ci- C 2 o)alkyl, cycloalkyl substituted alkyl, (C 2 -C 2 o)alkenyl, (C 2 -C 2 o)alkynyl, aryl, alkyl substituted aryl, arylalkyl, and aryl substituted arylalkyl, wherein one or more of the carbon atoms in the R 2 groups can be independently replaced with non-peroxide oxygen, sulfur or NR 8 , wherein R 8 is hydrogen, or an (Ci- Cjo) alkyl group, wherein the alkyl,
  • v --' represents 1, 2, or 3, optional double bonds, or a pharmaceutically acceptable salt or ester thereof.
  • the present invention provides for the use of a compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof to prepare a medicament for preventing and treating pain in a mammal (e.g., a human).
  • a mammal e.g., a human
  • FIG. 1 is an illustration of a synthetic route to prepare compounds used in' " the disclosed method.
  • FIG. 2 is an illustration of a synthetic route to prepare the compound VPC01091-C.
  • FIG. 3 is a graphical representation of the results from administration of a compound of formula VPCO 1091.
  • FIG. 4 is a graphical representation of the results from administration of a vehicle control.
  • FIG. 5 is a graphical representation of the results from a sciatic nerve injury preclinical model of neuropathic pain.
  • SlP sphingosine-1- phosphate
  • GPCR G-protein coupled receptor
  • SAR structure-activity relationship
  • EDG endothelial cell differentiation gene
  • EAE experimental autoimmune encephalomyelitis
  • NOD non-obese diabetic
  • TNF ⁇ tumor necrosis factor alpha
  • HDL high density lipoprotein
  • RT-PCR reverse transciptase polymerase chain reaction
  • the articles “a” and “an” are used herein to” refer to one or to more than one ⁇ e.g., to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • the term "affected cell” refers to a cell of a subject afflicted with a disease or disorder, which affected cell has an altered phenotype relative to a subject not afflicted with a disease or disorder. Cells or tissue are "affected” by a disease or disorder if the cells or tissue have an altered phenotype relative to the same cells or tissue in a subject not afflicted with a disease or disorder.
  • a disease or disorder is "alleviated” if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced.
  • An" analog of a chemical compound is a compound that, by way of example, resembles another in structure but is not necessarily an isomer ⁇ e.g., 5- fluorouracil is an analog of thymine).
  • a “test” cell, tissue, sample, or subject is one being examined or treated.
  • a “control” cell, tissue, sample, or subject is a cell, tissue, sample, or subject of the same type as a test cell, tissue, sample, or subject.
  • the control may, for example, be examined at precisely or nearly the same time the test cell, tissue, sample, or subject is examined.
  • the control may also, for example, be examined at a time distant from the time at which the test cell, tissue, sample, or subject is examined, and the results of the examination of the control may be recorded so that the recorded results may be compared with results obtained by examination of a test cell, tissue, sample, or subject.
  • the control may also be obtained from another source or similar source other than the test group or a test subject, where the test sample is obtained from a subject suspected of having a disease or disorder for which the test is being performed.
  • a "pathoindicative" cell, tissue, or sample is one which, when present, is an indication that the animal in which the cell, tissue, or sample is located (or from which the tissue was obtained) is afflicted with a disease or disorder. For example, the presence of one or more breast cells in a lung tissue of an animal is an indication that the. animal is afflicted with metastatic breast cancer.
  • a tissue "normally comprises” a cell if one or more of the cell are present in the tissue in an animal not afflicted with a disease or disorder.
  • the word “detect” and its grammatical variants refer to measurement of the species without quantification.
  • the terms “detect” and ''identify” are used interchangeably herein.
  • the words “determine” or “measure” and their grammatical variants refer to measurement of the species with quantification.
  • the terms “determine” or “measure” are used interchangeably herein.
  • a "detectable marker” or a “reporter molecule” is an atom or a molecule that permits the specific detection of a compound comprising the marker in the presence of similar compounds without a marker.
  • detectable markers or reporter molecules include, e.g., radioactive isotopes, antigenic determinants, enzymes, nucleic acids available for hybridization, chromophores, fluorophores, chemiluminescent molecules, electrochemically detectable molecules, and molecules that provide for altered fluorescence-polarization or altered light-scattering.
  • a "disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.
  • a "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.
  • an effective amount means an amount sufficient to produce a selected effect.
  • an effective amount of an SlP receptor antagonist is an amount that decreases the cell signaling activity of the SlP receptor.
  • a "functional" molecule is a molecule in a form in which it exhibits a property by which it is characterized.
  • a functional enzyme is one which exhibits the catalytic activity by which the enzyme is characterized.
  • inhibitor refers to the ability of a compound to reduce or impede a described function. Preferably, inhibition is by at least 10%, more preferably by at least 25%, even more preferably by at least 50%, and most preferably, the function is inhibited by at least 75%.
  • the term "instructional material” includes a publication, a recording,- a diagram, or any other medium of expression, which can be used to communicate the usefulness, in the kit for effecting alleviation of the various diseases or disorders ⁇ recited herein.
  • the instructional material may describe one or more methods of alleviating the diseases or disorders in a cell or a tissue of a mammal.
  • the instructional material of the kit may, for example, be affixed to a container which contains an active compound or be shipped together with a container which contains an active compound. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and an active compound be used cooperatively by the recipient.
  • parenteral means not through the alimentary canal but by some other route such as subcutaneous, intramuscular, intraspinal, or intravenous.
  • pharmaceutically acceptable carrier includes any of the standard pharmaceutical carriers, e.g., a phosphate buffered saline solution, water and emulsions such as an oil/water or water/oil emulsion, and various types of wetting agents.
  • purified and similar terms relate to the isolation of a molecule or compound in a form that is substantially free (at least 60% free, preferably 75% free, and most preferably 90% free) from other components normally associated with the molecule or compound in a native environment.
  • sample refers preferably to a biological sample from a subject, including, but not limited to, normal tissue samples, diseased tissue samples, biopsies, blood, saliva, feces, semen, tears, and urine.
  • a sample can also be any other source of material obtained from a subject that contains cells, tissues, or a fluid of interest.
  • a sample can also be obtained from a cell or tissue culture.
  • Standard or “control” are used (interchangeably herein and refer to something used for comparison.
  • a standard can be a known standard agent or compound which is administered or added to a control sample and used for comparing results when measuring said compound in a test sample.
  • Standard can also refer to an "internal standard,” such as an agent or compound which is added at known amounts to a sample and is useful in determining such things as purification or recovery rates when a sample is processed or subjected to purification or extraction procedures before a marker of interest is measured.
  • a "subject" of analysis, diagnosis, or treatment is an animal. Such animals include mammals, preferably a human.
  • a “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology for the purpose of diminishing or eliminating those signs.
  • a “therapeutically effective amount” of a compound is that amount of compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered.
  • treating includes prophylaxis of the specific disorder or condition, or alleviation of the symptoms associated with a specific disorder or condition and/or preventing or eliminating said symptoms.
  • the term "pharmaceutically acceptable carrier” includes any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, hydroxypropyl beta-cyclodextrins (HO-propyl beta cyclodextrins), water, emulsions such as an oil/water or water/oil emulsion, and various types of wetting agents.
  • the term also encompasses any of the agents approved by a regulatory agency of the U.S. Federal government or listed in the U.S. Pharmacopeia for use in animals, including humans.
  • the term "pharmaceutically-acceptable salt” refers to salts which retain the biological effectiveness and properties of compounds for practicing the disclosed method and which are not biologically or otherwise undesirable.
  • the compounds for practicing the disclosed method are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • alkyl by itself or as part of another substituent means a straight or branched aliphatic chain having the stated number of carbon atoms.
  • halo or halogen includes brorho, chloro, fluoro, and iodo.
  • haloalkyl refers to an alkyl radical bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl or trifluoromethyl and the like.
  • alkyl or C 1 -Cj O alkyl represents a branched or linear alkyl group having from one to six carbon atoms.
  • Ci-Cio alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, t- butyl, pentyl, hexyl, heptyl, octyl, and the like.
  • lower alkyl refers to branched or straight chain alkyl groups comprising one to about six carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl and the like.
  • alkenyl or C 2 -C1 0 alkenyl represents an olefinically unsaturated branched or linear group having from 2 to 10 carbon atoms and at least one double bond.
  • examples of such groups include, but are not limited to, 1-propenyl, 2- propenyl, 1, 3-butadienyl, 1-butenyl, hexenyl, pentenyl, and the like.
  • alkynyl or C 2 -C1 0 alkynyU refers to an unsaturated branched or linear group having from 2 to 10 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 1-pentynyl, and the like.
  • C 3 -Cs cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • substituents are each independently selected.
  • substituents may be the same or different than other substituents.
  • aryl refers to a mono or bicyclic C 5 -C 10 carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, benzyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.
  • optionally substituted aryl includes aryl compounds having from zero to four substituents, and a “substituted aryl” includes aryl compounds having one to four substituents, wherein the substituents include groups such as, for example, alkyl, halo or amino substituents.
  • arylalkyl refers to any aryl group which is attached to the parent moiety via the alkyl group, e.g., aryl(Ci-C 8 alkyl).
  • C 5 -C 6 arylXCs-Cg alkyl refers to a five or six membered aromatic ring that is attached to the parent moiety via the Cs-Cg alkyl group.
  • heterocyclic group refers to an optionally substituted mono- or bicyclic carbocyclic ring system containing from one to three heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, and nitrogen.
  • heteroaryl refers to an optionally substituted mono- or bicyclic carbocyclic ring system having one or two aromatic rings containing from one to three heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, and nitrogen.
  • heteroaryl rings include, but are not limited to, furyl, thienyl, pyridyl and the like.
  • bicyclic represents either an unsaturated or saturated stable 7- to 12-membered bridged or fused bicyclic carbon ring.
  • the bicyclic ring may be attached at any carbon atom which affords a stable structure.
  • the term includes, but is not limited to, naphthyl, dicyclohexyl, dicyclohexenyl, and the like.
  • EC50 of an agent refers to that concentration of an agent at which a given activity, including binding of sphingosine or other ligand of an S IP receptor and/or a functional activity of a S IP receptor (e.g., a signaling activity), is 50% maximal for that S IP receptor.
  • the EC50 is the concentration of agent that gives 50% activation, when 100% activation is set at the amount of activity of the S IP receptor which does not increase with the addition of more ligand/agonist and 0% is set at the amount of activity in the assay in the ' absence of added ligand/agonist.
  • phosphate analog and phosphonate analog comprise analogs of phosphate and phosphonate wherein the phosphorous atom is in the +5 oxidation state and one or more of the oxygen atoms is replaced with a non-oxygen moiety, including for example, the phosphate analogs phosphorothioate, phosphoro- dithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phosphoranilidate, phosphorami date, boronophosphates, and the like, including associated counterions, e.g., hydrogen, NEU, Na, and the like if such counterions are present.
  • counterions e.g., hydrogen, NEU, Na, and the like if such counterions are present.
  • the compounds for practicing the disclosed method may exist in tautomeric forms and include both mixtures and separate individual tautomers.
  • the following structure :
  • the terms 16:0, 18:0, 18:1, 20:4 or 22:6 hydrocarbon refers to a branched or straight alkyl or alkenyl group, wherein the first integer represents the total number of carbons in the group and the second integer represent the number of double bonds in the group.
  • an "SlP modulating agent” refers to a compound or composition that is capable of inducing a detectable change in SlP receptor activity in vivo or in vitro ⁇ e.g., at least 10% increase or decrease in S IP activity as measured by a given assay such as the bioassay described in the examples and known in the art.
  • SlP receptor refers to all of the SlP receptor subtypes (for example, the SlP receptors SlPi, SlP 2 , SlP 3 , SlP 4 , and SlP 5 ), unless the specific subtype is indicated.
  • the SlP analogs for practicing the disclosed method can contain one or more asymmetric centers in the molecule. A structure that does not designate the stereochemistry is to be understood as embracing all the various optical isomers, as well as racemic mixtures thereof.
  • the disclosed method includes the use of sphingosine 1-phosphate (SlP) analogs that have activity as receptor agonists at one or more S IP receptors, specifically the SlPi, S IP 4 and S IP 5 receptor types.
  • SlP sphingosine 1-phosphate
  • the disclosed method also includes compounds that have a phosphate moiety as well as compounds with hydrolysis-resistant phosphate surrogates such as phosphonates, ⁇ /p/j ⁇ -substituted phosphonates particularly where the alpha substitution is a halogen and phosphothionates.
  • the S IP receptor agonists have the general structure of Formula (IIA):
  • the R 2 group is selected from the group consisting of alkyl, alkenyl, alkynyl, alkyl substituted aryl, alkyl substituted cycloalkyl, arylalkyl and arylalkyl substituted aryl.
  • R 2 the chain lengths of 5-8 carbon atoms are preferred, or a pharmaceutically acceptable salt thereof.
  • the compounds having formula (II) can have R 1 selected from the group consisting of H, halo (e.g., F or Cl), methyl, tri-fluoromethyl, ethyl, propyl or other lower alkyl (Ci - Ce) or halo-, hydroxy-, alk ⁇ xy-, cyano- substituted lower alkyl group, and R 2 selected from the group consisting of.
  • R 1 selected from the group consisting of H, halo (e.g., F or Cl), methyl, tri-fluoromethyl, ethyl, propyl or other lower alkyl (Ci - Ce) or halo-, hydroxy-, alk ⁇ xy-, cyano- substituted lower alkyl group
  • R 2 selected from the group consisting of.
  • alkyl alkenyl, alkynyl, alkyl (optionally substituted aryl), alkyl (optionally substituted cycloalkyl), arylalkyl, and arylalkyl (optionally substituted aryl) with chain lengths of 5-8 carbon atoms preferred.
  • the invention provides a method for treating neuropathic pain including administering to a subject in need thereof of a therapeutically acceptable amount of a compound of formula (I) or formula (II), or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or formula (II), and a pharmaceutically-acceptable carrier.
  • the disclosed method also includes the use of pharmaceutical compositions including a compound of formula (I) or formula (II), and a pharmaceutically-acceptable carrier.
  • the compounds of formula (I) or formula (II) can be formulated as pharmaceutical compositions using standard pharmaceutically acceptable carriers, fillers, solubilizing agents and stabilizers known to those skilled in the art.
  • a pharmaceutical composition comprising a compound of formula (I) or formula (II), or analog, derivative, or modification thereof, as described herein, is used to administer the compound to a subject.
  • a specific value for a lower alkyl group is ethyl or propyl.
  • a specific value for halo is fluorine or chlorine.
  • a specific value for X is hydroxy or OPO 3 H 2 .
  • a specific value for R 1 is hydrogen.
  • a specific value for R 2 is C 5 -C 8 alkyl.
  • R 2 is octyl, or — O-heptyl.
  • R 2 is octyl.
  • n is 1 or 2.
  • Specific cycloalkyl groups having a double bond include:
  • a compound for practicing the disclosed method has an R z group placed para to the cycloalkyl ring.
  • a specific compound for practicing the disclosed method has the R 1 group placed ortho or meta to R 2 .
  • a specific compound for practicing the disclosed method has the R 2 group placed para to the benzylic cycloalkyl group ⁇ e.g., 1,4).
  • esters of the disclosed compounds include compounds where the X group is,
  • Y is selected from the group consisting of O, CH 2 , CHOH, CHF, CF 2 , and
  • R 9 and R 10 are independently selected from the group consisting alkoxy, alkenyloxy, alkynyloxy, aryloxy,
  • R 11 O— R 11 , c/X/NH* and - wherein R . ⁇ i selected from the group consisting of Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, and optionally substituted aryl. Particularly preferred R 9 and R 10 groups are alkoxy,
  • a specific compound of formula (II) is VPCO 1091, where X is OH, R 1 is hydrogen, RR 22 iiss ooccttaannee ((CC 88 HHii 7 ), n is 2, and the R 2 group is in the p ⁇ r ⁇ -positio ⁇ on the phenyl ring.
  • the formula is:
  • VPCO 1091 has two chiral centers (the quaternary carbon and benzylic carbon that is part of the cyclopentyl ring) and thus four isomers (diastereomers) are conceivable. VPCO 1091 is a mixture of these four isomers but the relative amount of each isomer is not known, but available evidence indicates that the four isomers are present in about equal amounts.
  • the individual isomers, A-D have the formulas:
  • Another specific compound of formula (II) is VPC01211 where X is OPO 3 H2, R 1 is hydrogen, R 2 is octane (CsHi 7 ), n is 2, and the R 2 group is in the para- position on the phenyl ring.
  • the formula is:
  • VPC02162 Another specific compound of formula (II) is VPC02162, where X is OH, R 1 is hydrogen, R 2 is octane (CgHi 7 ), n is 2, and the R 2 group is in the met ⁇ -position on the phenyl ring.
  • the formula is:
  • the present invention also provides a method for the use of esters of the compounds of formula (I) or formula (S), e.g., phosphate esters or phosphonate esters as described herein.
  • the disclosed method includes' pharmaceutically acceptable salts of the compounds of formula (I) or formula (II).
  • the disclosed method provides all possible isomers of the structures described by formula (I) or formula (II), noting that when n is one (cyclobutane) the compound is symmetric and lacks chiral centers, but cis and trans forms exist.
  • compositions comprising one or more disclosed compounds can be administered to a subject in need thereof by any number of routes and means including, but not limited to, topical, oral, buccal, intravenous, intramuscular, intra arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, vaginal, ophthalmic, pulmonary, or rectal means.
  • routes and means including, but not limited to, topical, oral, buccal, intravenous, intramuscular, intra arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, vaginal, ophthalmic, pulmonary, or rectal means.
  • the oral route is typically employed for most conditions requiring the disclosed compounds. Preference is given to intravenous injection or infusion for the acute treatments.
  • the oral or parenteral, e.g. intramuscular or subcutaneous, route is
  • the disclosed compounds can be administered at varying doses and at varying times, depending on such conditions as the health, age, weight, and sex of the subject.
  • the disclosed compounds can be administered to a subject via different routes.
  • the method provides administration of a composition that includes a disclosed compound, or an analog, derivative, or modification thereof, and albumin, e.g., the composition comprises at least one disclosed compound, a pharmaceutically acceptable carrier and 0.1-1.0% albumin.
  • Albumin can function as a buffer to improve the solubility of the compounds. In one aspect, albumin is not added.
  • the pharmaceutical compositions useful for practicing the disclosed method may be administered to deliver a dose of between 1 ng/kg/day and 100 mg/kg/day. In another embodiment, the pharmaceutical compositions useful for practicing the disclosed method may be administered to deliver a dose of between 1 ng/kg/day and 100 g/kg/day.
  • Pharmaceutically acceptable carriers which are useful include, but are not limited to; glycerol, water, saline, ethanol, and other pharmaceutically acceptable salt solutions such as phosphates and salts of organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991 , Mack Publication Co., New Jersey).
  • the pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution.
  • This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein.
  • Such sterile injectable formulations may be prepared using a non toxic parenterally acceptable diluent or solvent, such as water or 1,3 butane diol, for example.
  • Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides.
  • compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology.
  • preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.
  • compositions for administration to humans in order to prepare the compositions for administration to various animals are well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation.
  • Subjects to which administration of the pharmaceutical compositions of the disclosed method is contemplated include, but are not limited to, humans and other primates, and mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs.
  • a pharmaceutical composition may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses.
  • a "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is ⁇ generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • compositions will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions may further comprise one or more additional pharmaceutically active agents.
  • additional agents include anti-emetics and scavengers such as cyanide and cyanate scavengers.
  • Controlled- or sustained-release formulations of a pharmaceutical composition may be made using conventional technology.
  • the dosage forms to be used can be provided as slow or controlled-release of one or more active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying ' proportions.
  • Controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions.
  • single unit dosage forms for oral administration such as tablets, capsules, gelcaps, and caplets that are adapted for controlled-release are encompassed by the disclosed method.
  • Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • Powdered and granular formulations of a pharmaceutical preparation may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.
  • an "oily" liquid is one which comprises a carbon- containing liquid molecule and which exhibits a less polar character than water.
  • a formulation of a pharmaceutical composition for oral administration may be prepared, packaged, or sold in the form of a discrete solid dose unit including, but not limited to, a tablet, a hard or soft capsule, a cachet, a troche, or a lozenge, each containing a predetermined amount of the active ingredient.
  • Other formulations for oral administration include, but are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an aqueous or oily solution, a paste, a gel, a toothpaste, a mouthwash, a coating, an oral rinse, or an emulsion.
  • oral rinse and mouthwash are used interchangeably herein.
  • the disclosed method includes a kit comprising a compound or composition useful for preventing or treating pain in a subject and an instructional material which describes administering the compound or a composition comprising the compound to a cell or an animal.
  • a kit comprising a (preferably sterile) solvent for dissolving or suspending the disclosed composition prior to administering the compound to a cell or an animal.
  • the animal is a human.
  • the disclosed compounds having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a disclosed compound, which possess the useful properties described herein is included. It is known in the art how to prepare optically active forms (for example, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, by chiral synthesis, or chromatographic separation using a chiral stationary phase) and how to determine SlP agonist activity using the standard tests described herein, or using other similar tests which are well known in the art.
  • salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate, and ⁇ -glycerophosphate.
  • Inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • Salts derived from inorganic bases include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines,' trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycl
  • amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.
  • Non-limiting examples of amines include isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2- dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • carboxylic acid derivatives would be • useful in to practice the disclosed method, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the like.
  • Salts may be obtained using standard procedures well known in the art. For example reaction of a sufficiently basic compound such as an amine with an acid can afford a physiologically acceptable anion.
  • Alkali metal for example, sodium, potassium or lithium
  • alkaline earth metal for example calcium
  • salts of organic (e.g., carboxylic) acids can also be made.
  • O.23g palladium(II) acetate (0.1 eq) and 0.23g antimony(III) chloride (0.1 eq) were added to 80 mL acetic acid solution of 2-cyclo ⁇ enten-l-one 0.82g (10 mmol), 4-iodophenylboronic acid 2.48g (10 mmol) and sodium acetate 1.6g (20 mmol) under N 2 atmosphere. After being stirred for 24 hours at 25 0 C, the black precipitation was filtered off and the filtrate was diluted with 250 mL of brine, and then extracted twice with 50 mL methylene chloride.
  • the mixture of isomers of compound VPCOl 091 is preformed using a Chiralpak AD-H 4.6 mm ID x 250 mm column, at 45°C, solvent flow rate: 0.8 mL/min (isocratic), solvent: 95% heptane : 2.5% ethanol : 2.5% methanol (0.2% diethylamine added as modifier to 95:2.5:2.5 mixture).
  • the run time was 40 min, UVi, wavelength monitored: 254nm.
  • the order of isomer elution was D, C, B, and A.
  • Test compound VPC01091 (Drug T, mixture of all isomers), was dissolved in 2% hydroxypropyl beta-cyclodextrin in water and administered to the test group of laboratory rats.
  • the vehicle (Drug V: 2% hydroxypropyl beta-cyclodextrin in water) was administered to the control group of laboratory rats. Each group included 11 animals.
  • VPC01091 -D was demonstrated to be effective at blocking mechanical allodynia associated with nerve injury in two preclinical models of neuropathic pain, sciatic nerve injury (CCI) and spinal nerve injury (SNL) models using groups of rats (7).
  • CCI sciatic nerve injury
  • SNL spinal nerve injury
  • oral treatment with VPCOl 091 -D was started 2 weeks following nerve injury, once the pain was established.
  • a control group received only vehicle.
  • VPC01091-D (3mg/kg, p.o.) reversed mechanical allodynia by 42 ⁇ 8% in the CCI model. (See Figure 5).
  • VPC01091-D (3 mg/kg, p.o.) produced similar analgesic activity (50 ⁇ 10%) in the SNL model.
  • Oral duloxetine a drug approved for the treatment of neuropathic pain, produces a similar degree of analgesic efficacy in both models at a dose of 30 mg/kg, p.o.

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Abstract

L'invention concerne des composés et des méthodes utilisés pour prévenir et traiter une douleur, par exemple, une douleur neuropathique, chez un sujet. Lesdits composés peuvent être des agents 'modulant le SPP' capables d'induire un changement détectable dans une activité de récepteur SlP.
PCT/US2007/002422 2006-01-27 2007-01-29 Méthode de traitement pour douleur neuropathique WO2007089715A2 (fr)

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JP2008552487A JP2009528274A (ja) 2006-01-27 2007-01-29 神経因性疼痛の治療法
AU2007209961A AU2007209961A1 (en) 2006-01-27 2007-01-29 Method for treatment of neuropathic pain
BRPI0707281-3A BRPI0707281A2 (pt) 2006-01-27 2007-01-29 método para prevenção ou tratamento de dor neuropática em um mamìfero
MX2008009579A MX2008009579A (es) 2006-01-27 2007-01-29 Metodo para el tratamiento de dolor neuropatico.
CA002640366A CA2640366A1 (fr) 2006-01-27 2007-01-29 Methode de traitement pour douleur neuropathique
EP07717121A EP1986623A2 (fr) 2006-01-27 2007-01-29 Méthode de traitement pour douleur neuropathique
IL193040A IL193040A0 (en) 2006-01-27 2008-07-24 Method for treatment of neuropathic pain
US12/179,816 US8008286B2 (en) 2006-01-27 2008-07-25 Method for treatment of neuropathic pain

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US60/762,589 2006-01-27

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EP2177521A1 (fr) 2008-10-14 2010-04-21 Almirall, S.A. Nouveaux dérivés de 2-amidothiadiazole
EP2202232A1 (fr) 2008-12-26 2010-06-30 Laboratorios Almirall, S.A. Dérivés du 1,2,4-oxadiazole et leur application thérapeutique
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EP1986623A2 (fr) 2008-11-05
AU2007209961A1 (en) 2007-08-09
CN101378741A (zh) 2009-03-04
US20090062238A1 (en) 2009-03-05
ZA200806349B (en) 2009-06-24
KR20080086546A (ko) 2008-09-25
MX2008009579A (es) 2008-09-25
BRPI0707281A2 (pt) 2011-04-26
IL193040A0 (en) 2009-02-11
WO2007089715A3 (fr) 2007-09-27
JP2009528274A (ja) 2009-08-06
CA2640366A1 (fr) 2007-08-09
RU2008134702A (ru) 2010-03-10
US8008286B2 (en) 2011-08-30

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